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Difficulty: MediumInfectious Disease Mechanisms

An 8-year-old boy, who recently arrived from a region with disrupted healthcare infrastructure, is evaluated in the emergency department for a low-grade fever, severe sore throat, and difficulty breathing. Physical examination reveals a tightly adherent, grayish pseudomembrane covering the tonsils and extending into the posterior pharynx. The pathogen responsible for this patient's clinical presentation produces a potent A-B type exotoxin. Arrange the following steps of this exotoxin's cellular mechanism of action in the correct chronological order, beginning with its initial interaction with the host cell.

  1. 1Binding of the B subunit to the heparin-binding epidermal growth factor receptor on the host cell membrane
  2. 2Internalization of the toxin-receptor complex via receptor-mediated endocytosis
  3. 3Acidification of the endosome and subsequent translocation of the A subunit into the cytosol
  4. 4Covalent transfer of ADP-ribose from NAD+ to elongation factor 2 (EF-2)
  5. 5Arrest of host cell protein synthesis and subsequent cell death

Answer

The correct chronological sequence begins with receptor binding, followed by endocytosis, endosomal acidification driving translocation, ADP-ribosylation of EF-2, and finally the arrest of cellular protein synthesis.
Diphtheria toxin is a classic A-B exotoxin with a pathogenesis dictated by a strict chronological sequence. First, the binding (B) subunit attaches to a specific host cell receptor. The entire toxin-receptor complex is then internalized via endocytosis. As the endosome naturally acidifies, a structural conformational change occurs, driving the active (A) subunit through the endosomal membrane and into the cytosol. Once in the cytoplasm, the A subunit acts enzymatically to catalyze the ADP-ribosylation of elongation factor 2 (EF-2), a protein essential for tRNA translocation during mRNA translation. This permanent modification inactivates EF-2, resulting in a complete halt of protein synthesis, which ultimately leads to cellular necrosis. Clinically, this necrosis manifests as the classical pharyngeal pseudomembrane.

Step-by-Step Solution

1
Identify the pathogen and its specific virulence factor based on the clinical vignette.
The patient has respiratory diphtheria, caused by Corynebacterium diphtheriae, which produces diphtheria toxin (an A-B exotoxin).
The grayish, firmly adherent pseudomembrane in an unimmunized patient is a classic clinical hallmark of diphtheria.
2
Determine the initial step of the A-B toxin's interaction with the host.
The B subunit must first bind to the host cell receptor (heparin-binding EGF-like growth factor).
Exotoxins cannot exert intracellular toxic effects without first recognizing and attaching to a susceptible target cell.
3
Trace the internalization process of the bound complex.
The bound toxin is internalized via receptor-mediated endocytosis into an endosome.
This is the primary eukaryotic cellular mechanism for the uptake of large receptor-bound complexes.
4
Identify how the catalytically active component reaches its target in the cytosol.
Endosomal acidification triggers the translocation of the A subunit across the endosomal membrane.
The acidic environment is required to induce the necessary conformational change that releases the catalytic A subunit into the cytoplasm.
5
Determine the molecular target and the ultimate cellular consequence.
The A subunit ADP-ribosylates EF-2, which halts protein synthesis and results in cell death.
Inactivation of EF-2 prevents the translocation of the ribosome along mRNA, representing the definitive toxic mechanism that causes tissue necrosis (the pseudomembrane).

Key Concept

The cellular pathogenesis of diphtheria toxin (an A-B exotoxin) involves receptor binding, endocytosis, acid-mediated translocation, and ADP-ribosylation of elongation factor 2 (EF-2).
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Infectious Disease Mechanisms

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